Field of the Invention
This invention relates to the field of methods for preparing a lyophilized lipid composition and gas-filled microspheres. The lyophilized lipid composition is especially useful in the preparation of gas-filled microspheres in accordance with the methods of the present invention. Microspheres prepared by these methods are particularly suitable, for example, in ultrasonic imaging applications and in therapeutic delivery systems.
Background of the Invention
Preparations of conventional lipids and lipid blends are generally dispersed to a standard of uniformity by dispersion of the product in organic solvents such as cyclohexane:ethanol mixtures, followed by freezing and subsequent drying in vacuo (freeze drying) to yield a mixture. Conventional preparations of lipid dispersions or dry lipid blends are limited by process of making them whereby the lipids are solvated in organic solvents with dissimilar physical properties (i.e. solubility coefficients, polarity) to water or aqueous-based formulations. This presents a problem as the dispersions are very difficult to rehydrate with aqueous-based formulations. In addition, the standard of uniformity is extremely low, unlike the consistent uniformity exemplified by the ratio of the lipids of the present invention throughout the lipid composition. The time and ability to rehydrate conventional dispersions into a pharmaceutically acceptable preparation is severely limited. Oftentimes, lipid particles do not hydrate adequately and remain as undispersed, insoluble, pharmaceutically unacceptable formulations and the inability of the lipid particles to be sterile filtered through one or more 0.2 .mu.m filters. The lipid preparations of the prior art are not sufficiently dispersed and subsequently can not be filtered from the solution when the dispersion is filtered through a 0.22 .mu.m filter. The unfiltered moieties result in batch to batch variation of the ratio of lipids in the composition. The lipid dispersions are often processed to determine the total lipids ultimately dispersed into the formulations. This process is not acceptable because it often leads to formulations that are difficult to prepare and the resulting formulations are of unknown lipid quantity. In addition, the manufacturing process is inefficient and ineffective due to the time and cost of the process. These and/or problems have been addressed in the present invention.